According to the National Cancer Institute SEER, the US death rate from cancer for all races (2000 2003) is 241.5 per 100,000 men and 163.5 per 100,000 women. Breast cancer is the most frequent cancer among women with more than 200,000 new cases per year and approximately 40,000 cancer deaths per year. Recurrent metastatic disease is the leading cause of death. There is growing evidence that suggests that the presence of circulating tumor cells (CTC) is a predictor of metastatic disease and poor clinical outcomes. The elimination or even reduction of CTCs may result in a significant improvement in patient survival. CTCs are a rare tumor cell population among circulating white blood cells and are difficult to eradicate by conventional therapies. We propose to develop a system that utilizes extracorporeal venous to venous circulation to thermo-ablate these CTCs in a continuous flow loop a process we call thermopheresis. Bringing the circulation outside the body renders CTCs much more accessible to intervention. The ablation will be made specific to the cancer cells by tagging them with targeted, near- infrared absorbing nanoshells developed by Nanospectra and will occur within the proposed extracorporeal device, without the need for separation of the CTCs from the blood. Separately, Nanospectra is nearing clinical trials for a therapeutic medical device for the elimination of solid tumors, which also incorporates this new class of near-infrared-absorbing nanoshells. Solid tumor targeting of nanoshells has been demonstrated in animal models, and this work will utilize targeting molecules that allow selective binding to the CTCs and not to circulating white blood cells. In this proposal, therefore, we will demonstrate the feasibility of thermopheresis of CTCs using targeted nanoshell particles and a breast cancer cell line in a mock-up of the proposed extracorporeal device. These particles will be designed to selectively bind to SK-BR-3 cells (a breast cancer cell line), whereupon the cells will be ablated with externally applied laser energy. This will be accomplished through these readily achievable aims: (1) Demonstrate the ability to specifically target SK-BR-3 cells with nanoshell particles;(2) Demonstrate the ability to selectively thermoablate the targeted cells while maintaining the viability of untargeted bystanders in vitro using the particles developed in Aim 1;and (3) Derive the major design criteria for manufacturing a device to provide thermopheresis to cancer patients. If successful, we expect the combination of thermopheresis with other traditional cancer treatment modalities will lead to significantly improved patient outcome for breast cancer and ultimately for other malignancies as well. There is increasing evidence that the presence of circulating tumor cells (CTCs) is indicative of poor prognosis for certain cancers and, in particular, breast cancer. The causal relationship between the presence of CTCs and clinical outcomes is less direct, but there is circumstantial evidence that CTCs may impact both the persistence of ongoing disease as well as the likelihood of metastasis. We believe that the elimination or reduction in the number of CTCs will have a potentially therapeutic benefit by reducing such cells available to form metastatic colonies.